Targeted Alpha Therapy: Current Clinical Applications

Francisco D C Guerra Liberal, Joe M O'Sullivan, Stephen J McMahon, Kevin M Prise

Research output: Contribution to journalArticle

Abstract

α-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known regarding the mechanisms of action of α particles in this setting, and accurate assessments of the dosimetry underpinning their effectiveness are lacking. However, targeted alpha therapy (TAT) is gaining more attention as new targets, synthetic chemistry approaches, and α particle emitters are identified, constructed, developed, and realized. From a radiobiological perspective, α particles are more effective at killing cells compared to low linear energy transfer radiation. Also, from these direct effects, it is now evident from preclinical and clinical data that α emitters are capable of both producing effects in nonirradiated bystander cells and stimulating the immune system, extending the biological effects of TAT beyond the range of α particles. The short range of α particles makes them a potent tool to irradiate single-cell lesions or treat solid tumors by minimizing unwanted irradiation of normal tissue surrounding the cancer cells, assuming a high specificity of the radiopharmaceutical and good stability of its chemical bonds. Clinical approval of 223RaCl2 in 2013 was a major milestone in the widespread application of TAT as a safe and effective strategy for cancer treatment. In addition, 225Ac-prostate specific membrane antigen treatment benefit in metastatic castrate-resistant prostate cancer patients, refractory to standard therapies, is another game-changing piece in the short history of TAT clinical application. Clinical applications of TAT are growing with different radionuclides and combination therapies, and in different clinical settings. Despite the remarkable advances in TAT dosimetry and imaging, it has not yet been used to its full potential. Labeled 227Th and 225Ac appear to be promising candidates and could represent the next generation of agents able to extend patient survival in several clinical scenarios.

Original languageEnglish
JournalCancer biotherapy & radiopharmaceuticals
Early online date16 Jun 2020
DOIs
Publication statusEarly online date - 16 Jun 2020

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